Abstract. Positron Emission Tomography (PET) is a unique tool for investigating the living brain and is used in many research fields and clinical practice to quantify molecular components of neurotransmitter systems as well as the incorporation or metabolism of specific compounds through the injection of tracer doses of radioactively labeled molecules that bind to a brain target. Current PET scanners, however, require the subject to lie still during scanning, and can only be used in centers large enough to support such a device. Newer portable PET cameras, such as CerePETTM (Brain Biosciences, Inc.), are paving the way for a wide array of novel applications, including quantifying metabolic and neurochemical responses to environmental cues relevant to psychiatric/neurological diseases and performing PET close to sites where brain injury occurs. The device?s enhanced sensitivity over current scanners can also result in reduced required injected dose of tracer, greatly facilitating longitudinal assessments of disease progression. Portable scanners can radically transform PET applications, and developing analytic methods for data collected using these devices is critical to facilitate a broader valid use of quantitative PET. A significant limitation in the use of portable PET devices, and PET imaging in general, is the need for arterial blood sampling from the subject?s arm during scan, for current gold- standard quantification of tracer uptake and binding to the target in relation to tracer blood levels. Arterial blood sampling carries risks and is uncomfortable for the subject being imaged. Our group has been developing new methods to estimate outcome measures from PET data, including using simultaneous modeling across multiple brain regions to quantify tracers with reversible kinetics in absence of blood data or a reference region. We seek here to develop a new method to quantify the net influx rate of PET tracers with irreversible kinetics using only PET images. We will gather PET and arterial blood data in 20 healthy volunteers, who will be imaged at rest in two separate scans in two different PET cameras, A) a current PET camera (Siemens BiographTM mCT) and B) the portable CerePETTM, after a bolus infusion of [18F]fluorodeoxyglucose (18F-FDG), a tracer with irreversible kinetics that is the most widely used to quantify glucose metabolism. We propose to: 1) Develop a new tissue-based, blood-free method to quantify the net influx rate of PET irreversible tracers, and optimize it for application with short scan times, common in clinical settings; 2) Validate the method in comparison to arterial blood-based quantification using the newly collected 18F-FDG data; 3) Develop and disseminate a library of software routines for implementation of the validated method for use with current and portable PET scanners, to allow its incorporation into pipelines for analysis of brain imaging data. This method can significantly help widen the application of fully quantitative PET imaging with 18F-FDG and other tracers with irreversible kinetics, and enhance PET contribution to understanding the molecular underpinnings of brain disorders, and identifying clinically useful biomarkers.